Summary: 2Fe-2S iron-sulfur cluster binding domain
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Succinate dehydrogenase Edit Wikipedia article
|succinate dehydrogenase (succinate-ubiquinone oxidoreductase)|
The structure of SQR in a phospholipid membrane. SdhA, SdhB, SdhC and SdhD
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
Succinate dehydrogenase or succinate-coenzyme Q reductase (SQR) or respiratory Complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain.
In step 6 of the citric acid cycle, SQR catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. This occurs in the inner mitochondrial membrane by coupling the two reactions together.
- 1 Structure
- 2 Mechanism
- 3 Inhibitors
- 4 Role in disease
- 5 See also
- 6 References
Mitochondrial and many bacterial monomer SQRs are composed of four subunits: two hydrophilic and two hydrophobic. The first two subunits, a flavoprotein (SdhA) and an iron-sulfur protein (SdhB), are hydrophilic. SdhA contains a covalently attached flavin adenine dinucleotide (FAD) cofactor and the succinate binding site and SdhB contains three iron-sulfur clusters: [2Fe-2S], [4Fe-4S], and [3Fe-4S]. The second two subunits are hydrophobic membrane anchor subunits, SdhC and SdhD. Human mitochondria contain two distinct isoforms of SdhA (Fp subunits type I and type II), these isoforms are also found in Ascaris suum and Caenorhabditis elegans. The subunits form a membrane-bound cytochrome b complex with six transmembrane helices containing one heme b group and a ubiquinone-binding site, which can be seen in Image 4. Two phospholipid molecules, one cardiolipin and one phosphatidylethanolamine, are also found in the SdhC and SdhD subunits (not shown in the image). They serve to occupy the hydrophobic space below the heme b. These subunits are displayed in image 3. SdhA is green, SdhB is teal, SdhC is fuchsia, and SdhD is yellow. Around SdhC and SdhD is a phospholipid membrane with the intermembrane space at the top of the image.
Table of subunit composition
|No.||Subunit name||Human protein||Protein description from UniProt||Pfam family with Human protein|
|1||SdhA||SDHA_HUMAN||Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial||Pfam PF00890, Pfam PF02910|
|2||SdhB||SDHB_HUMAN||Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial||Pfam PF13085, Pfam PF13183|
|3||SdhC||C560_HUMAN||Succinate dehydrogenase cytochrome b560 subunit, mitochondrial||Pfam PF01127|
|4||SdhD||DHSD_HUMAN||Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial||Pfam PF05328|
Ubiquinone binding site
Ubiquinone’s binding site, image 4, is located in a gap composed of SdhB, SdhC, and SdhD. Ubiquinone is stabilized by the side chains of His207 of subunit B, Ser27 and Arg31 of subunit C, and Tyr83 of subunit D. The quinone ring is surrounded by Ile28 of subunit C and Pro160 of subunit B. These residues, along with Il209, Trp163, and Trp164 of subunit B, and Ser27 (C atom) of subunit C, form the hydrophobic environment of the quinone-binding pocket (not shown in the image).
Succinate binding site
SdhA provides the binding site for the oxidation of succinate. The side chains Thr254, His354, and Arg399 of subunit A stabilize the molecule while FAD oxidizes and carries the electrons to the first of the iron-sulfur clusters, [2Fe-2S]. This can be seen in image 5.
The succinate-binding site and ubiquinone-binding site are connected by a chain of redox centers including FAD and the iron-sulfur clusters. This chain extends over 40 Å through the enzyme monomer. All edge-to-edge distances between the centers are less than the suggested 14 Å limit for physiological electron transfer. This electron transfer is demonstrated in image 8.
Little is known about the exact succinate oxidation mechanism. However, the crystal structure shows that FAD, Glu255, Arg286, and His242 of subunit A (not shown) are good candidates for the initial deprotonation step. Thereafter, there are two possible elimination mechanisms: E2 or E1cb. In the E2 elimination, the mechanism is concerted. The basic residue or cofactor deprotonates the alpha carbon, and FAD accepts the hydride from the beta carbon, oxidizing the bound succinate to fumarate—refer to image 6. In E1cb, an enolate intermediate is formed, shown in image 7, before FAD accepts the hydride. Further research is required to determine which elimination mechanism succinate undergoes in Succinate Dehydrogenase. Oxidized fumarate, now loosely bound to the active site, is free to exit the protein.
After the electrons are derived from succinate oxidation via FAD, they tunnel along the [Fe-S] relay until they reach the [3Fe-4S] cluster. These electrons are subsequently transferred to an awaiting ubiquinone molecule within the active site. The Iron-Sulfur electron tunneling system is shown in image 9.
The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of subunit D. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of subunit C. Following the first single electron reduction step, a semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol. This mechanism of the ubiquinone reduction is shown in image 8.
Heme prosthetic group
Although the functionality of the heme in succinate dehydrogenase is still being researched, some studies[by whom?] have asserted that the first electron delivered to ubiquinone via [3Fe-4S] may tunnel back and forth between the heme and the ubiquinone intermediate. In this way, the heme cofactor acts as an electron sink. Its role is to prevent the interaction of the intermediate with molecular oxygen to produce reactive oxygen species (ROS). The heme group, relative to ubiquinone, is shown in image 4.
It has also been proposed that a gating mechanism may be in place to prevent the electrons from tunneling directly to the heme from the [3Fe-4S] cluster. A potential candidate is residue His207, which lies directly between the cluster and the heme. His207 of subunit B is in direct proximity to the [3Fe-4S] cluster, the bound ubiquinone, and the heme; and could modulate electron flow between these redox centers.
To fully reduce the quinone in SQR, two electrons as well as two protons are needed. It has been argued that a water molecule (HOH39) arrives at the active site and is coordinated by His207 of subunit B, Arg31 of subunit C, and Asp82 of subunit D. The semiquinone species is protonated by protons delivered from HOH39, completing the ubiquinone reduction to ubiquinol. His207 and Asp82 most likely facilitate this process. Other studies claim that Tyr83 of subunit D is coordinated to a nearby histidine as well as the O1 carbonyl oxygen of ubiquinone. The histidine residue decreases the pKa of tyrosine, making it more suitable to donate its proton to the reduced ubiquinone intermediate.
There are two distinct classes of inhibitors of complex II: those that bind in the succinate pocket and those that bind in the ubiquinone pocket. Ubiquinone type inhibitors include carboxin and thenoyltrifluoroacetone. Succinate-analogue inhibitors include the synthetic compound malonate as well as the TCA cycle intermediates, malate and oxaloacetate. Indeed, oxaloacetate is one of the most potent inhibitors of Complex II. Why a common TCA cycle intermediate would inhibit Complex II is not entirely understood, though it may exert a protective role in minimizing reverse-electron transfer mediated production of superoxide by Complex I.. Atpenin 5a are highly potent Complex II inhibitors mimicking ubiquinone binding.
Ubiquinone type inhibitors have been used as fungicides in agriculture since the 1960s. Carboxin was mainly used to control disease caused by basidiomycetes such as stem rusts and Rhizoctonia diseases. More recently, other compounds with a broader spectrum against a range of plant pathogens have been developed including boscalid, penthiopyrad and fluopyram. Some agriculturally important fungi are not sensitive towards members of the new generation of ubiquinone type inhibitors 
Role in disease
The fundamental role of succinate-coenzyme Q reductase in the electron transfer chain of mitochondria makes it vital in most multicellular organisms, removal of this enzyme from the genome has also been shown to be lethal at the embryonic stage in mice.
- SdhA mutations can lead to Leigh syndrome, mitochondrial encephalopathy, and optic atrophy.
- SdhB mutations can lead to tumorogenesis in chromaffin cells, causing a class of tumors known as succinate dehydrogenase deficient including hereditary paraganglioma and hereditary pheochromocytoma, succinate dehydrogenase deficient renal carcinoma and succinate dehydrogenase deficient gastrointestinal stromal tumor (GIST). Tumors tend to be malignant. It can also lead to decreased life-span and increased production of superoxide ions.
- SdhC mutations can lead to decreased life-span, increased production of superoxide ions, hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign. These mutations are uncommon.
- SdhD mutations can lead to hereditary paraganglioma and hereditary pheochromocytoma. Tumors tend to be benign, and occur often in the head and neck regions. These mutations can also decrease life-span and increase production of superoxide ions.
Mammalian succinate dehydrogenase functions not only in mitochondrial energy generation, but also has a role in oxygen sensing and tumor suppression; and, therefore, is the object of ongoing research.
Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, are observed post mortem in the brains of patients with Huntington's Disease, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients.
- Oyedotun KS, Lemire BD (March 2004). "The quaternary structure of the Saccharomyces cerevisiae succinate dehydrogenase. Homology modeling, cofactor docking, and molecular dynamics simulation studies". The Journal of Biological Chemistry. 279 (10): 9424–31. PMID 14672929. doi:10.1074/jbc.M311876200.
- Tomitsuka E, Hirawake H, Goto Y, Taniwaki M, Harada S, Kita K (August 2003). "Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase)". Journal of Biochemistry. 134 (2): 191–5. PMID 12966066. doi:10.1093/jb/mvg144.
- Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S (January 2003). "Architecture of succinate dehydrogenase and reactive oxygen species generation". Science. 299 (5607): 700–4. PMID 12560550. doi:10.1126/science.1079605.
- Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z (July 2005). "Crystal structure of mitochondrial respiratory membrane protein complex II". Cell. 121 (7): 1043–57. PMID 15989954. doi:10.1016/j.cell.2005.05.025.
- Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S (March 2006). "Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction". The Journal of Biological Chemistry. 281 (11): 7309–16. PMID 16407191. doi:10.1074/jbc.M508173200.
- Kenney WC (April 1975). "The reaction of N-ethylmaleimide at the active site of succinate dehydrogenase". The Journal of Biological Chemistry. 250 (8): 3089–94. PMID 235539.
- Tran QM, Rothery RA, Maklashina E, Cecchini G, Weiner JH (October 2006). "The quinone binding site in Escherichia coli succinate dehydrogenase is required for electron transfer to the heme b". The Journal of Biological Chemistry. 281 (43): 32310–7. PMID 16950775. doi:10.1074/jbc.M607476200.
- Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (January 2008). "High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates". The Biochemical Journal. 409 (2): 491–9. PMID 17916065. doi:10.1042/BJ20071162.
- Avenot HF, Michailides TJ (2010). "Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi". Crop Protection. 29 (7): 643. doi:10.1016/j.cropro.2010.02.019.
- Dubos T, Pasquali M, Pogoda F, Casanova A, Hoffmann L, Beyer M (January 2013). "Differences between the succinate dehydrogenase sequences of isopyrazam sensitive Zymoseptoria tritici and insensitive Fusarium graminearum strains". Pesticide Biochemistry and Physiology. 105 (1): 28–35. doi:10.1016/j.pestbp.2012.11.004.
- Barletta JA, Hornick JL (2012). "Succinate dehydrogenase-deficient tumors: diagnostic advances and clinical implications". Advances in Anatomic Pathology. 19 (4): 193–203. PMID 22692282. doi:10.1097/PAP.0b013e31825c6bc6.
- Skillings EA, Morton AJ (2016). "Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington's Disease". Journal of Huntington's Disease. 5 (1): 19–32. PMID 27031731. doi:10.3233/JHD-160189.
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2Fe-2S iron-sulfur cluster binding domain Provide feedback
The 2Fe-2S ferredoxin family have a general core structure consisting of beta(2)-alpha-beta(2) which abeta-grasp type fold. The domain is around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated.
Internal database links
|SCOOP:||DHODB_Fe-S_bind Fer2 Fer2_2 Fer2_4 Fer4_8|
|Similarity to PfamA using HHSearch:||Fer2 Fer2_4|
This tab holds annotation information from the InterPro database.
InterPro entry IPR025192
This entry represents the 2Fe-2S iron-sulphur cluster binding domain found in members of the succinate dehydrogenase/fumarate reductase protein family. The domain is around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||electron carrier activity (GO:0009055)|
|iron-sulfur cluster binding (GO:0051536)|
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The 2Fe-2S ferredoxin family have a general core structure consisting of beta(2)-alpha-beta(2) which abeta-grasp type fold. The domani is around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated.
The clan contains the following 5 members:DHODB_Fe-S_bind Fer2 Fer2_2 Fer2_3 Fer2_4
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Key: available, not generated, — not available.
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|Number in seed:||38|
|Number in full:||4898|
|Average length of the domain:||108.90 aa|
|Average identity of full alignment:||38 %|
|Average coverage of the sequence by the domain:||41.36 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
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There are 9 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Fer2_3 domain has been found. There are 110 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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